ResearchPad - brain https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Inferring a simple mechanism for alpha-blocking by fitting a neural population model to EEG spectra]]> https://www.researchpad.co/article/elastic_article_13836 One of the most striking features of the human electroencephalogram (EEG) is the presence of neural oscillations in the range of 8-13 Hz. It is well known that attenuation of these alpha oscillations, a process known as alpha blocking, arises from opening of the eyes, though the cause has remained obscure. In this study we infer the mechanism underlying alpha blocking by fitting a neural population model to EEG spectra from 82 different individuals. Although such models have long held the promise of being able to relate macroscopic recordings of brain activity to microscopic neural parameters, their utility has been limited by the difficulty of inferring these parameters from fits to data. Our approach involves fitting eyes-open and eyes-closed EEG spectra in a way that minimizes unnecessary differences in model parameters between the two states. Surprisingly, we find that changes in just one parameter, the level of external input to the inhibitory neurons in cortex, is sufficient to explain the attenuation of alpha oscillations. This indicates that opening of the eyes reduces alpha activity simply by increasing external inputs to the inhibitory neurons in the cortex.

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<![CDATA[Early correction of synaptic long-term depression improves abnormal anxiety-like behavior in adult GluN2B-C456Y-mutant mice]]> https://www.researchpad.co/article/elastic_article_13831 Mice that carry a heterozygous, autism spectrum disorder-risk C456Y mutation in the NMDA receptor (NMDAR) subunit GluN2B show decreased protein levels, hippocampal NMDAR currents, and NMDAR-dependent long-term depression and have abnormal anxiolytic-like behavior. Early, but not late, treatment of the young mice with the NMDAR agonist D-cycloserine rescues these phenotypes.

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<![CDATA[Functional magnetic resonance imaging of the trail-making test in older adults]]> https://www.researchpad.co/article/elastic_article_13819 The trail-making test (TMT) is a popular neuropsychological test, which is used extensively to measure cognitive impairment associated with neurodegenerative disorders in older adults. Behavioural performance on the TMT has been investigated in older populations, but there is limited research on task-related brain activity in older adults. The current study administered a naturalistic version of the TMT to a healthy older-aged population in an MRI environment using a novel, MRI-compatible tablet. Functional MRI was conducted during task completion, allowing characterization of the brain activity associated with the TMT. Performance on the TMT was evaluated using number of errors and seconds per completion of each link. Results are reported for 36 cognitively healthy older adults between the ages of 52 and 85. Task-related activation was observed in extensive regions of the bilateral frontal, parietal, temporal and occipital lobes as well as key motor areas. Increased age was associated with reduced brain activity and worse task performance. Specifically, older age was correlated with decreased task-related activity in the bilateral occipital, temporal and parietal lobes. These results suggest that healthy older aging significantly affects brain function during the TMT, which consequently may result in performance decrements. The current study reveals the brain activation patterns underlying TMT performance in a healthy older aging population, which functions as an important, clinically-relevant control to compare to pathological aging in future investigations.

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<![CDATA[An Update on the Complexity and Importance of Accurately Diagnosing Post-Traumatic Stress Disorder and Comorbid Traumatic Brain Injury]]> https://www.researchpad.co/article/elastic_article_12392 As awareness for diagnosing and screening patients for trauma has grown, more effective evidence-based treatments are available to treat post-traumatic stress disorder (PTSD). Despite these gains, several patients are non-responsive to care and research has shifted to determining barriers for cure or improvement. With the advent of modern warfare, the combination of intermittent explosive devices and more robust armor has resulted in service members surviving blasts that historically would have been lethal, resulting in a rise in traumatic brain injuries (TBIs). Post-traumatic stress disorder and TBI are often comorbid and can serve as the aforementioned barriers for cure or improvement for each other if one goes unrecognized. This mini-review will discuss the importance of diagnosing both entities, especially when they are comorbid, by examining how misdiagnosis may interfere with treatment outcomes. Several recent advances in methods to successfully distinguish between the two disorders will be reviewed.

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<![CDATA[Thalamic, cortical, and amygdala involvement in the processing of a natural sound cue of danger]]> https://www.researchpad.co/article/elastic_article_7872 When others stop and silence ensues, animals respond as if threatened. This study highlights the brain areas involved in listening to the dangerous silence.

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<![CDATA[克唑替尼联合脑转移灶切除、全脑放疗治疗ROS1阳性伴有症状脑转移的肺腺癌]]> https://www.researchpad.co/article/5c0528cad5eed0c48489ce0a 伴有脑转移的肺癌预后差。克唑替尼可有效治疗ROS1(C-ros oncogene 1 receptor tyrosine kinase)融合基因阳性的肺癌, 但由于血脑屏障通透率较低, 对脑转移灶的治疗效果不佳。本文总结1例综合运用手术、全脑放疗+残留灶补量放疗及克唑替尼等手段治疗ROS1融合基因阳性伴有症状脑转移的肺腺癌患者, 并对其有效性及安全性进行讨论和分析。方法采用手术切除占位效应明显、引起头疼症状的颅内病灶, 获得病理; 因ROS1融合基因阳性, 给予克唑替尼治疗, 250 mg, 2次/d; 术后进行全脑放疗+残留灶补量放疗。按照实体瘤疗效评价标准1.1版(Response Evaluation Criteriation in Solid Tumours, RECIST v1.1)评价客观疗效。按照不良反应通用术语标准4.0版(Common Terminology Criteria for Adverse Events v4.0, CTC AE v4.0)评估用药期间发生的不良事件。结果该患者服用克唑替尼3个月后, 肺部病变接近完全缓解(complete remission, CR), 颅内病变部分缓解(partial response, PR), 腹腔病变CR, 视物模糊症状减轻。结论综合运用手术、全脑放疗+残留灶补量放疗、克唑替尼治疗ROS1融合基因阳性伴有症状脑转移的肺腺癌患者, 可有效控制颅内颅外病灶, 耐受性好。 ]]> <![CDATA[EGFR-TKI治疗非小细胞肺癌中枢神经系统转移的进展]]> https://www.researchpad.co/article/5c0528c8d5eed0c48489cd93 约50%的非小细胞肺癌会出现中枢神经系统转移,从而导致不良预后。非小细胞肺癌患者中存在表皮生长因子受体(epidermal growth factor receptor, EGFR)突变,这部分患者对EGFR酪氨酸激酶抑制剂(EGFRtyrosine kinase inhibitors, EGFR-TKI)的治疗显示出了良好的耐受性及疗效。EGFR-TKI对非小细胞肺癌中枢神经系统转移也显示出了一定的疗效。本文针对EGFR-TKI药物对于非小细胞肺癌中枢神经系统转移的治疗进展进行综述。

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<![CDATA[非小细胞肺癌脑膜转移的临床病理特征及预后分析]]> https://www.researchpad.co/article/5c0528c6d5eed0c48489cd11 脑膜转移(leptomeningeal metastasis, LM)是晚期非小细胞肺癌(non-small cell lung cancer, NSCLC)严重并发症之一, 生活质量降低, 预后差。本研究旨在探讨NSCLC-LM患者的临床病理特征及预后。方法回顾性分析2015年1月-2016年6月首都医科大学附属北京朝阳医院收治的3例NSCLC-LM患者的临床资料, 并结合文献进行分析。结果3例患者均为肺腺癌, 且表皮生长因子受体(epidermal growth factor receptor, EGFR)21外显子L858R突变(mutations, m), 其中男性1例, 女性2例; 年龄59岁-64岁, 平均年龄61.3岁, 主要临床表现及查体:头痛(3/3)、头晕(3/3)、恶心呕吐(3/3)、癫痫(2/3)、复视(1/3)、听力下降(1/3)、脑膜刺激征(3/3)。出现症状到LM确诊时间为1个月-4个月(平均2.3个月)。除了1例肺癌和LM同时诊断, 2例分别在EGFR酪氨酸激酶抑制剂(tyrosine kinase inhibitors, TKIs)和化疗进展后出现LM, 肺癌到LM平均确诊时间为8.5个月。3例患者脑增强磁共振成像(magnetic resonance imaging, MRI)均显示软脑膜线性强化; 3例脑脊液中找到癌细胞, 其中2例行EGFR检测, 均为EGFR 21外显子L858R突变。2例患者接受TKIs治疗, 症状好转, 其中1例联合替莫唑胺, 无进展生存期(progression-free survival, PFS)达4.9个月, 总生存时间(overall survival, OS)为13.9个月。结论EGFRm肺腺癌可能易出现LM; NSCLC-LM症状不典型, 易漏诊、误诊; TKIs联合替莫唑胺可能是EGFRm-NSCLC-LM的治疗选择。 ]]> <![CDATA[全脑放疗时间对<i>EGFR</i>突变非小细胞肺癌脑转移患者生存的影响]]> https://www.researchpad.co/article/5c0528c4d5eed0c48489cc94 全脑放疗(whole brain radiotherapy, WBRT)在表皮生长因子受体(epidermal growth factor receptor, EGFR)突变的非小细胞肺癌(non-small cell lung cancer, NSCLC)脑转移患者治疗中何时应用尚无高级别的循证医学证据。本研究旨在探讨WBRT的参与时间对携有EGFR突变的NSCLC脑转移患者生存的影响。方法2009年8月-2015年5月在我院确诊的EGFR突变伴脑转移的晚期NSCLC共78例患者,均接受WBRT及EGFR酪氨酸激酶抑制剂(EGFR tyrosine kinase inhibitors, EGFR-TKIs)治疗的48例初治患者进入临床分析,采用Cox比例风险模型分析患者颅内无进展生存期(progression-free survival, PFS)及总生存期(overall survival, OS)的影响因素。结果全组患者颅内客观缓解率(objective response rate, ORR)为81.3%,颅内疾病控制率(disease control rate, DCR)为93.8%,中位颅内PFS为10个月,中位OS为18个月。颅内PFS的多因素分析显示,美国东部肿瘤协作组评分(Eastern Cooperative Oncology Group performance status, ECOG PS)0分-1分(HR=30.436, 95%CI: 4.721-196.211, P < 0.001)及早期WBRT患者(HR=3.663, 95%CI: 1.657-8.098, P=0.001)的颅内PFS更佳。OS的多因素分析显示,ECOG PS 0分-1分(HR=57.607, 95%CI: 6.135-540.953, P < 0.001)、早期WBRT(HR=2.757, 95%CI: 1.140-6.669, P=0.024)及立体定向放射外科(stereotaxic radio surgery, SRS)的应用(HR=5.964, 95%CI: 1.895-18.767, P=0.002)是患者OS的独立预后因素。结论早期WBRT联合TKIs治疗可改善EGFR突变的NSCLC脑转移患者的预后,尚有待大样本的前瞻性临床试验验证。 ]]> <![CDATA[肺癌硬膜下脊髓外转移患者临床特征分析]]> https://www.researchpad.co/article/5c0528c0d5eed0c48489cb9b 肺癌硬膜下脊髓外转移罕见, 可导致严重的神经损害, 本研究旨在阐明其临床特征。方法2013年5月-2016年5月, 北京协和医院8例确诊硬膜下脊髓外转移肺癌患者纳入该研究, 系统回顾分析临床资料。结果7例非小细胞肺癌及1例小细胞肺癌合并硬膜下脊髓外转移。马尾综合征是最常见的临床表现。行腰椎穿刺的5例(100%)患者脑脊液找到肿瘤细胞。脊髓增强核磁(magnetic resonance imaging, MRI)发现, 3例软脊膜弥漫线样增强, 4例硬膜下脊髓外多发结节, 1例具有上述两种表现。4例接受靶向治疗和/或放疗患者神经系统症状改善或稳定。中位生存时间是5.8个月。结论硬膜下脊髓外转移需依靠神经系统症状及增强MRI影像学检查诊断。靶向治疗和/或放疗可能有效。 ]]> <![CDATA[Reference values of physiological 18F-FET uptake: Implications for brain tumor discrimination]]> https://www.researchpad.co/article/N80bdbd58-ef10-47b0-8bc3-8bde8c3b2b52

Purpose

The aim of this study was to derive reference values of 18F-fluoro-ethyl-L-tyrosine positron emission tomography (18F-FET-PET) uptake in normal brain and head structures to allow for differentiation from tumor tissue.

Materials and methods

We examined the datasets of 70 patients (median age 53 years, range 15–79), whose dynamic 18F-FET-PET was acquired between January 2016 and October 2017. Maximum standardized uptake value (SUVmax), target-to-background standardized uptake value ratio (TBR), and time activity curve (TAC) of the 18F-FET-PET were assessed in tumor tissue and in eight normal anatomic structures and compared using the t-test and Mann-Whitney U-test. Correlation analyses were performed using Pearson or Spearman coefficients, and comparisons between several variables with Pearson’s chi-squared tests and Kruskal-Wallis tests as well as the Benjamini-Hochberg correction.

Results

All analyzed structures showed an 18F-FET uptake higher than background (threshold: TBR > 1.5). The venous sinuses and cranial muscles exhibited a TBR of 2.03±0.46 (confidence interval (CI) 1.92–2.14), higher than the uptake of caudate nucleus, pineal gland, putamen, and thalamus (TBR 1.42±0.17, CI 1.38–1.47). SUVmax, TBR, and TAC showed no difference in the analyzed structures between subjects with high-grade gliomas and subjects with low-grade gliomas, except the SUVmax of the pineal gland (t-tests of the pineal gland: SUVmax: p = 0.022; TBR: p = 0.411). No significant differences were found for gender and age.

Conclusion

Normal brain tissue demonstrates increased 18F-FET uptake compared to background tissue. Two distinct clusters have been identified, comprising venous structures and gray matter with a reference uptake of up to SUVmax of 2.99 and 2.33, respectively.

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<![CDATA[Proteomic analysis of protein composition of rat hippocampus exposed to morphine for 10 days; comparison with animals after 20 days of morphine withdrawal]]> https://www.researchpad.co/article/N2838fdc6-dc33-429a-ba0d-e2e831e6a950

Opioid addiction is recognized as a chronic relapsing brain disease resulting from repeated exposure to opioid drugs. Cellular and molecular mechanisms underlying the ability of organism to return back to the physiological norm after cessation of drug supply are not fully understood. The aim of this work was to extend our previous studies of morphine-induced alteration of rat forebrain cortex protein composition to the hippocampus. Rats were exposed to morphine for 10 days and sacrificed 24 h (groups +M10 and −M10) or 20 days after the last dose of morphine (groups +M10/−M20 and −M10/−M20). The six altered proteins (≥2-fold) were identified in group (+M10) when compared with group (−M10) by two-dimensional fluorescence difference gel electrophoresis (2D-DIGE). The number of differentially expressed proteins was increased to thirteen after 20 days of the drug withdrawal. Noticeably, the altered level of α-synuclein, β-synuclein, α-enolase and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was also determined in both (±M10) and (±M10/−M20) samples of hippocampus. Immunoblot analysis of 2D gels by specific antibodies oriented against α/β-synucleins and GAPDH confirmed the data obtained by 2D-DIGE analysis. Label-free quantification identified nineteen differentially expressed proteins in group (+M10) when compared with group (−M10). After 20 days of morphine withdrawal (±M10/−M20), the number of altered proteins was increased to twenty. We conclude that the morphine-induced alteration of protein composition in rat hippocampus after cessation of drug supply proceeds in a different manner when compared with the forebrain cortex. In forebrain cortex, the total number of altered proteins was decreased after 20 days without morphine, whilst in hippocampus, it was increased.

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<![CDATA[A new simple brain segmentation method for extracerebral intracranial tumors]]> https://www.researchpad.co/article/Nb837d809-9647-425d-8dfd-2c3174a6dd80

Normal brain segmentation is available via FreeSurfer, Vbm, and Ibaspm software. However, these software packages cannot perform segmentation of the brain for patients with brain tumors. As we know, damage from extracerebral tumors to the brain occurs mainly by way of pushing and compressing while leaving the structure of the brain intact. Three-dimensional (3D) imaging, augmented reality (AR), and virtual reality (VR) technology have begun to be applied in clinical practice. The free medical open-source software 3D Slicer allows us to perform 3D simulations on a computer and requires little user interaction. Moreover, 3D Slicer can integrate with the third-party software mentioned above. The relationship between the tumor and surrounding brain tissue can be judged, but accurate brain segmentation cannot be performed using 3D Slicer. In this study, we combine 3D Slicer and FreeSurfer to provide a novel brain segmentation method for extracerebral tumors. This method can help surgeons identify the “real” relationship between the lesion and adjacent brain tissue before surgery and improve preoperative planning.

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<![CDATA[Resting state networks of the canine brain under sevoflurane anaesthesia]]> https://www.researchpad.co/article/N0f88adec-494f-4799-9601-5a30499e23df

Resting-state functional Magnetic Resonance Imaging (rs-fMRI) has become an established technique in humans and reliably determines several resting state networks (RSNs) simultaneously. Limited data exist about RSN in dogs. The aim of this study was to investigate the RSNs in 10 healthy beagle dogs using a 3 tesla MRI scanner and subsequently perform group-level independent component analysis (ICA) to identify functionally connected brain networks. Rs-fMRI sequences were performed under steady state sevoflurane inhalation anaesthesia. Anaesthetic depth was titrated to the minimum level needed for immobilisation and mechanical ventilation of the patient. This required a sevoflurane MAC between 0.8 to 1.2. Group-level ICA dimensionality of 20 components revealed distributed sensory, motor and higher-order networks in the dogs’ brain. We identified in total 7 RSNs (default mode, primary and higher order visual, auditory, two putative motor-somatosensory and one putative somatosensory), which are common to other mammals including humans. Identified RSN are remarkably similar to those identified in awake dogs. This study proves the feasibility of rs-fMRI in anesthetized dogs and describes several RSNs, which may set the basis for investigating pathophysiological characteristics of various canine brain diseases.

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<![CDATA[The role of the immune system in driving neuroinflammation]]> https://www.researchpad.co/article/N146eda4d-7bf1-4a56-94e1-27482c4c4efb

Neuroinflammation is now recognised as an important contributory factor in the progression of Alzheimer’s disease and probably also in the early stages of the disease. It is likely that this derives largely from aberrant activation of microglia, the resident mononuclear phagocytes of the brain. These cells are responsible for physiological immune surveillance and clearance of pathogens in the central nervous system, but evidence indicates that in Alzheimer’s disease, microglial function is compromised, and this contributes to the pathology. It is unclear what factors cause the inappropriate activation of the microglia in Alzheimer’s disease, but one contributor may be infiltrating peripheral immune cells and these include macrophages and T cells. It has been suggested that both cell types modulate the phenotype of microglia, highlighting the importance of crosstalk between the innate and adaptive immune system in Alzheimer’s disease. This review outlines our current knowledge of how cells of the peripheral immune system, specifically macrophages and T cells, may modulate microglial phenotype in the context of Alzheimer’s disease and considers the impact on their function, especially phagocytic capacity.

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<![CDATA[Influence of mild-moderate hypocapnia on intracranial pressure slow waves activity in TBI]]> https://www.researchpad.co/article/N9a06315a-84fe-4dcc-a451-1ed4a7e0fee2

Background

In traumatic brain injury (TBI) the patterns of intracranial pressure (ICP) waveforms may reflect pathological processes that ultimately lead to unfavorable outcome. In particular, ICP slow waves (sw) (0.005–0.05 Hz) magnitude and complexity have been shown to have positive association with favorable outcome. Mild-moderate hypocapnia is currently used for short periods to treat critical elevations in ICP. Our goals were to assess changes in the ICP sw activity occurring following sudden onset of mild-moderate hypocapnia and to examine the relationship between changes in ICP sw activity and other physiological variables during the hypocapnic challenge.

Methods

ICP, arterial blood pressure (ABP), and bilateral middle cerebral artery blood flow velocity (FV), were prospectively collected in 29 adult severe TBI patients requiring ICP monitoring and mechanical ventilation in whom a minute volume ventilation increase (15–20% increase in respiratory minute volume) was performed as part of a clinical CO2-reactivity test. The time series were first treated using FFT filter (pass-band set to 0.005–0.05 Hz). Power spectral density analysis was performed. We calculated the following: mean value, standard deviation, variance and coefficient of variation in the time domain; total power and frequency centroid in the frequency domain; cerebrospinal compliance (Ci) and compensatory reserve index (RAP).

Results

Hypocapnia led to a decrease in power and increase in frequency centroid and entropy of slow waves in ICP and FV (not ABP). In a multiple linear regression model, RAP at the baseline was the strongest predictor for the decrease in the power of ICP slow waves (p < 0.001).

Conclusion

In severe TBI patients, a sudden mild-moderate hypocapnia induces a decrease in mean ICP and FV, but also in slow waves power of both signals. At the same time, it increases their higher frequency content and their morphological complexity. The difference in power of the ICP slow waves between the baseline and the hypocapnia period depends on the baseline cerebrospinal compensatory reserve as measured by RAP.

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<![CDATA[Coagulopathy after hemorrhagic traumatic brain injury, an observational study of the incidence and prognosis]]> https://www.researchpad.co/article/N1dd13e08-7cb3-4f61-9033-8e1de5bd5639

Background

Traumatic brain injury is associated with high rates of mortality and morbidity. Trauma patients with a coagulopathy have a 10-fold increased mortality risk compared to patients without a coagulopathy. The aim of this study was to identify the incidence of coagulopathy and relate early coagulopathy to clinical outcome in patients with traumatic intracranial hemorrhages.

Methods

Between September 2015 and December 2016, 108 consecutive cranial trauma patients with traumatic intracranial hemorrhages were included in this study. To assess the relationship between patients with a coagulopathy and outcome, a chi-squared test was performed.

Results

A total of 29 out of the 108 patients (27%) with a traumatic intracranial hemorrhage developed a coagulopathy within 72 h after admission. Overall, a total of 22 patients (20%) died after admission of which ten were coagulopathic at emergency department presentation. Early coagulopathy in patients with traumatic brain injury is associated with progression of hemorrhagic injury (odds ratio 2.4 (95% confidence interval 0.8–8.0)), surgical intervention (odds ratio 2.8 (95% confidence interval 0.87–9.35)), and increased in-hospital mortality (odds ratio 23.06 (95% confidence interval 5.5–95.9)).

Conclusion

Patients who sustained a traumatic intracranial hemorrhage remained at risk for developing a coagulopathy until 72 h after trauma. Patients who developed a coagulopathy had a worse clinical outcome than patients who did not develop a coagulopathy.

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<![CDATA[The impact of body posture on intrinsic brain activity: The role of beta power at rest]]> https://www.researchpad.co/article/N65f7a4e6-ac5f-46ef-91d2-3d4de84bb5d0

Tying the hands behind the back has detrimental effects on sensorimotor perceptual tasks. Here we provide evidence that beta band oscillatory activity in a resting state condition might play a crucial role in such detrimental effects. EEG activity at rest was measured from thirty young participants (mean age = 24.03) in two different body posture conditions. In one condition participants were required to keep their hands freely resting on the table. In the other condition, participants’ hands were tied behind their back. Increased beta power was observed in the left inferior frontal gyrus during the tied hands condition compared to the free hands condition. A control experiment ruled out alternative explanations for observed change in beta power, including muscle tension. Our findings provide new insights on how body postural manipulations impact on perceptual tasks and brain activity.

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<![CDATA[Polymer-fiber-coupled field-effect sensors for label-free deep brain recordings]]> https://www.researchpad.co/article/N12f161cb-ce31-436b-989e-fa44b0a6dffa

Electrical recording permits direct readout of neural activity but offers limited ability to correlate it to the network topography. On the other hand, optical imaging reveals the architecture of neural circuits, but relies on bulky optics and fluorescent reporters whose signals are attenuated by the brain tissue. Here we introduce implantable devices to record brain activities based on the field effect, which can be further extended with capability of label-free electrophysiological mapping. Such devices reply on light-addressable potentiometric sensors (LAPS) coupled to polymer fibers with integrated electrodes and optical waveguide bundles. The LAPS utilizes the field effect to convert electrophysiological activity into regional carrier redistribution, and the neural activity is read out in a spatially resolved manner as a photocurrent induced by a modulated light beam. Spatially resolved photocurrent recordings were achieved by illuminating different pixels within the fiber bundles. These devices were applied to record local field potentials in the mouse hippocampus. In conjunction with the raster-scanning via the single modulated beam, this technology may enable fast label-free imaging of neural activity in deep brain regions.

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<![CDATA[Dysregulation of multiple metabolic networks related to brain transmethylation and polyamine pathways in Alzheimer disease: A targeted metabolomic and transcriptomic study]]> https://www.researchpad.co/article/Nf62c48b8-7c01-44cc-9110-a611b974b3f9

Background

There is growing evidence that Alzheimer disease (AD) is a pervasive metabolic disorder with dysregulation in multiple biochemical pathways underlying its pathogenesis. Understanding how perturbations in metabolism are related to AD is critical to identifying novel targets for disease-modifying therapies. In this study, we test whether AD pathogenesis is associated with dysregulation in brain transmethylation and polyamine pathways.

Methods and findings

We first performed targeted and quantitative metabolomics assays using capillary electrophoresis-mass spectrometry (CE-MS) on brain samples from three groups in the Baltimore Longitudinal Study of Aging (BLSA) (AD: n = 17; Asymptomatic AD [ASY]: n = 13; Control [CN]: n = 13) (overall 37.2% female; mean age at death 86.118 ± 9.842 years) in regions both vulnerable and resistant to AD pathology. Using linear mixed-effects models within two primary brain regions (inferior temporal gyrus [ITG] and middle frontal gyrus [MFG]), we tested associations between brain tissue concentrations of 26 metabolites and the following primary outcomes: group differences, Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) (neuritic plaque burden), and Braak (neurofibrillary pathology) scores. We found significant alterations in concentrations of metabolites in AD relative to CN samples, as well as associations with severity of both CERAD and Braak, mainly in the ITG. These metabolites represented biochemical reactions in the (1) methionine cycle (choline: lower in AD, p = 0.003; S-adenosyl methionine: higher in AD, p = 0.005); (2) transsulfuration and glutathione synthesis (cysteine: higher in AD, p < 0.001; reduced glutathione [GSH]: higher in AD, p < 0.001); (3) polyamine synthesis/catabolism (spermidine: higher in AD, p = 0.004); (4) urea cycle (N-acetyl glutamate: lower in AD, p < 0.001); (5) glutamate-aspartate metabolism (N-acetyl aspartate: lower in AD, p = 0.002); and (6) neurotransmitter metabolism (gamma-amino-butyric acid: lower in AD, p < 0.001). Utilizing three Gene Expression Omnibus (GEO) datasets, we then examined mRNA expression levels of 71 genes encoding enzymes regulating key reactions within these pathways in the entorhinal cortex (ERC; AD: n = 25; CN: n = 52) and hippocampus (AD: n = 29; CN: n = 56). Complementing our metabolomics results, our transcriptomics analyses also revealed significant alterations in gene expression levels of key enzymatic regulators of biochemical reactions linked to transmethylation and polyamine metabolism. Our study has limitations: our metabolomics assays measured only a small proportion of all metabolites participating in the pathways we examined. Our study is also cross-sectional, limiting our ability to directly test how AD progression may impact changes in metabolite concentrations or differential-gene expression. Additionally, the relatively small number of brain tissue samples may have limited our power to detect alterations in all pathway-specific metabolites and their genetic regulators.

Conclusions

In this study, we observed broad dysregulation of transmethylation and polyamine synthesis/catabolism, including abnormalities in neurotransmitter signaling, urea cycle, aspartate-glutamate metabolism, and glutathione synthesis. Our results implicate alterations in cellular methylation potential and increased flux in the transmethylation pathways, increased demand on antioxidant defense mechanisms, perturbations in intermediate metabolism in the urea cycle and aspartate-glutamate pathways disrupting mitochondrial bioenergetics, increased polyamine biosynthesis and breakdown, as well as abnormalities in neurotransmitter metabolism that are related to AD.

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